Congestive heart failure chronic pharmacotherapy

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Chronic Pharmacotherapy in HFrEF

Diuretics
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Hydralazine
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ACC/AHA Guideline Recommendations

Initial and Serial Evaluation of the HF Patient
Hospitalized Patient
Patients With a Prior MI
Sudden Cardiac Death Prevention
Surgical/Percutaneous/Transcather Interventional Treatments of HF
Patients at high risk for developing heart failure (Stage A)
Patients with cardiac structural abnormalities or remodeling who have not developed heart failure symptoms (Stage B)
Patients with current or prior symptoms of heart failure (Stage C)
Patients with refractory end-stage heart failure (Stage D)
Coordinating Care for Patients With Chronic HF
Quality Metrics/Performance Measures

Implementation of Practice Guidelines

Congestive heart failure end-of-life considerations

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Patients who have concomitant disorders
Obstructive Sleep Apnea in the Patient with CHF
NSTEMI with Heart Failure and Cardiogenic Shock

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Sara Zand, M.D.[2] Rim Halaby, M.D. [3]

## Overview

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Pharmacotherapy is the mainstay of therapy for heart failure with reduced ejection fraction (HFrEF) and should be initiated before considering device therapy.Three major goals of therapy for patients with HFrEF including reduction in mortality, prevention of hospitalization due to worsening HF, and improvement in clinical status. Suppression of renin-angiotensin-aldosterone (RAAS) and sympathetic nervous systems with angiotensin-converting enzyme inhibitors (ACE-I) or an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, and mineralocorticoid receptor antagonists (MRA) have been shown to improve survival, reducing the risk of HF hospitalizations, and reducing symptoms in patients with HFrEF. ACE-I/ARNI, a beta-blocker, and an MRA are recommended as cornerstone therapies for these patients, unless the drugs are not tolerated or contraindicated. 2021 ESC Guideline recommends the use of ARNI as a replacement for ACE-I in symptomatic patients with ACE-I, beta-blocker, and MRA therapies. ARNI may be considered as a first-line therapy instead of an ACE-I. Angiotensin-receptor blockers (ARBs) are recommended in patients intolerant to ACEI or ARNI. The sodium-glucose co-transporter 2 (SGLT2) inhibitors including dapagliflozin and empagliflozin added to therapy with ACE-I/ ARNI/ beta-blocker/ MRA to reduce the risk of cardiovascular death and worsening HF in patients with HFrEF.

## Starting and target doses of medications and novel therapies for heart failure

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Betablockers | Starting dose | Target dose

|
|

Bisoprolol | 1.25 mg once daily  | 10 mg once daily
Carvedilol | 3.125 mg twice daily  | 25 mg twice daily for weight <85 kg and 50 mg

twice daily for weight≥ 85 kg

Metoprolol succinate | 12.5–25 mg daily  | 200 mg daily
ARNIs
Sacubitril/valsartan | 24/26 mg–49/51 mg twice daily  | 97/103 mg twice daily
ACEI
Captopril | 6.25 mg 3× daily  | 50 mg 3× daily
Enalapril | 2.5 mg twice daily  | 10–20 mg twice daily
Lisinopril | 2.5–5 mg daily  | 20–40 mg daily
Ramipril | 1.25 mg daily  | 10 mg daily
ARBs
Candesartan | 4–8 mg daily  | 32 mg daily
Losartan | 25–50 mg daily  | 150 mg daily
Valsartan | 40 mg twice daily  | 160 mg twice daily
Aldosterone antagonists
Eplerenone | 25 mg daily  | 50 mg daily
Spironolactone | 12.5–25 mg daily  | 25–50 mg daily
SGL2 ihibitors
Dapagliflozin  10 mg daily  | 10 mg daily  | 10 mg daily
Empagliflozin | 10 mg daily  | 10 mg daily
Vasodilators
Hydralazine | 25 mg 3× daily  | 75 mg 3× daily
Isosorbide dinitrate | 20 mg 3× daily  | 40 mg 3× daily
Fixed-dose combination isosorbide dinitrate/hydralazine | 20 mg/37.5 mg (1 tab) 3× daily  | 2 tabs 3× daily
Ivabradine
Ivabradine | 2.5–5 mg twice daily  | Titrate to heart rate 50–60 beats/min, Maximum dose 7.5 mg twice daily
The above table adopted from 2021 AHA/ACC Guideline

[1]

## Drugs recommended in all patients with heart failure with reduced ejection fraction

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### Medications indicated in patients with New York Heart Association (NYHA class II–IV) heart failure with reduced ejection fraction (LVEF ≤ 40%)

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Recommendations for HFrEF and NYHA class II–IV

(Class I, Level of Evidence A):

❑ ACE-I is recommended for patients with HFrEF to reduce the risk of HF hospitalization and death
❑ Beta-blocker is recommended for patients with stable HFrEF to reduce the risk of HF hospitalization and death
❑ MRA (Mineralocorticoid receptor antagonist) is recommended for patients with HFrEF to reduce the risk of HF hospitalization and death
❑ Dapagliflozin or empagliflozin are recommended for patients with HFrEF to reduce the risk of HF hospitalization and death

(Class I, Level of Evidence B):

❑ Sacubitril/valsartan is recommended as a replacement for an ACE-I in patients with HFrEF to reduce the risk of HF hospitalization and death

The above table adopted from 2021 ESC Guideline

[2]

### Angiotensin-converting enzyme inhibitors

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* ACE-Is are the first class of drugs that reduce mortality and morbidity in patients with HFrEF and improve symptoms.
* ACEI should be Uptitrated to the maximum tolerated recommended dose.

### Beta-blockers

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* Beta-blockers can reduce mortality and morbidity in patients with HFrEF, in addition to treatment with an ACE-I and diuretic and also improve symptoms.
* In symptomatic heart failure, ACE-I and beta-blockers can be used in combination.
* Initiation of a beta-blocker before an ACE-I and vice versa are not recommended.[3]
* Beta-blockers should be initiated in clinically stable, euvolaemic, patients at a low dose and gradually titrated to the maximum tolerated dose.
* After stability of hemodynamic in patients admitted with acute heart failure, beta-blockers should be cautiously initiated in hospital
* Use of betablocker in patients with HFrEF with AF was not associated with reduction in mortality or hospital admission.

### MRA or Mineralocorticoid receptor antagonists

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* In all patients with HFrEF, MRAs (spironolactone or eplerenone) are recommended, in addition to an ACE-I and a beta-blocker, to reduce mortality and the risk of heart failure hospitalization.[4]
* MRAs improve symptoms.
* MRAs block receptors that bind aldosterone and also other steroid hormones (corticosteroid and androgen) receptors.
* Eplerenone is more specific for aldosterone blockade and, therefore, causes less gynaecomastia.
* In patients with impaired renal function and in those with serum potassium concentrations >5.0 mmol/L, MRA should be used with causion.

### Angiotensin receptor-neprilysin inhibitor

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* In the PARADIGM-HF trial, sacubitril/valsartan, an ARNI, was superior to enalapril in reducing hospitalizations for worsening HF, cardiovascular mortality, and all-cause mortality in patients with ambulatory HFrEF with LVEF ≤ 40% (changed to <_35% during the study).[5]
* Patients with elevated plasma NP concentrations, an eGFR≥ 30 mL/min/1.73 m2 and were able to tolerate enalapril and then sacubitril/valsartan.
* Use of sacubitril/valsartan was associated with improvement in symptoms and quality of life a reduction in the incidence of diabetes requiring insulin treatment,[6]

and a reduction in the decline in eGFR [7]as well as a reduced rate of hyperkalemia[8].

* In addition, the need for loop diuretic reduced while using of sacubitril/valsartan.[9]
* Common side effect of sacubitril/valsartan is symptomatic hypotension as compared to enalapril, but despite developing hypotension, these patients also gained clinical benefits from sacubitril/valsartan therapy.
* The recommendation is that an ACE-I or ARB is replaced by sacubitril/valsartan in ambulatory patients with HFrEF, who remain symptomatic despite optimal treatment.
* Two studies have shown the use of ARNI in hospitalized patients with adequate blood pressure (BP), and an eGFR >_30 mL/min/1.73 m2, without previously treated with ACE-I, was associated with reduced subsequent cardiovascular death or HF hospitalizations.[10][11]

### Sodium-glucose co-transporter 2 inhibitors

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* The result of DAPA-HF trial showed the long-term effects of dapagliflozin (SGLT2 inhibitor) compared to placebo in addition to optimal medical therapy (OMT), on morbidity and mortality in patients with NYHA class II-IV, and had an LVEF≤ 40%.[12]
* Elevated plasma NT-proBNP and an eGFR >_30 mL/min/1.73 m2 were needed to initiation of therapy.
* Benefits of dapagliflozin in heart failure including:

* Reduction in worsening HF (hospitalization)
* Reduction in cardiovascular death.
* Reduction in all-cause mortality
* Alleviated HF symptomS
* Improvement of physical function and quality of life in patients with symptomatic HFrEF

* Benefits were seen early after the initiation of dapagliflozin.
* Survival benefits were seen in patients with HFrEF with and without diabetes.
* EMPEROR-Reduced trial investigated that empagliflozin reduced the combined primary endpoint of CV death or HF  hospitalization by 25% in patients with NYHA class II-IV symptoms, and an LVEF <_40% despiteOMT and eGFR >20 mL/min/1.73 m2.
* Reduction in the decline in eGFR and improvement in quality of life among patients receiving empagliflozin were also found.[13]
* Dapagliflozin or empagliflozin are recommended, in addition to OMT with an ACE-I/ARNI, a beta-blocker and an MRA, for patients with HFrEF regardless of diabetes status.
* The need for diuretic may be reduced due to The diuretic/natriuretic properties of SGLT2 inhibitors and reducing congestion.[14]
* The combined SGLT-1 and SGLT-2 inhibitors, sotagliflozin, has also been investigated in patients with diabetes who were hospitalized with HF.[15]
* Side effects of SGLT2 inhibitors including:

* Increased risk of recurrent genital fungal infections

* A small reversible reduction in eGFR following initiation

### Medications with reducing mortality in heart failure reduced EF

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* ACE-I/ARNI, betablocker, mineralocorticoid receptos antagonist, SGLT2 inhibitor

### Medications with reducing hospitalization in heart failure reduced EF

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* Diuretic, digoxin, ivabradine, hydralazine, isosorbide dinitrate

## Other medications in HFrEF in patients with NYHA 2-4

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Recommendations for heart failure with reduced ejection fraction and NYHA 2-4

Loop diuretics (Class I, Level of Evidence C):

❑ Loop diuretics are recommended in patients with HFrEF with signs and/or symptoms of congestion to improve HF symptoms, exercise capacity, and reduce HF hospitalizations

ARB (Class I, Level of Evidence B):

❑ ARB is recommended in symptomatic patients to reduce the risk of HF hospitalization and cardiovascular death for whom unable to tolerate an ACE-I or ARNI (patients should also receive a beta-blocker and MRA)

If-channel inhibitor :(Class IIa, Level of Evidence B) :

❑Ivabradine should be considered in symptomatic patients with LVEF ≤35%, sinus rhythm on ECG and a resting heart rate≥ 70 b.p.m despite treatment with maximum tolerated beta-blocker, ACE-I/(or ARNI), and an MRA, to reduce the risk of HF hospitalization and cardiovascular death

If-channel inhibitor : (Class IIa, Level of Evidence C)

❑ Ivabradine should be considered in symptomatic patients with LVEF≤ 35%, in sinus rhythm and a resting heart rate≥ 70 b.p.m. when can not tolerate or have contraindications for a beta-blocker, for reduction the risk of HF hospitalization and cardiovascular death. Patients should also receive an ACE-I (or ARNI) and MRA

Soluble guanylate cyclase receptor stimulator: (Class IIb, Level of Evidence B)

❑ Vericiguat may be considered in patients in NYHA class II-IV with worsening HF despite therapy with an ACE-I (or ARNI), a beta-blocker and MRA to reduce the risk of cardiovascular death or HF hospitalization

Hydralazine, isosorbide dinitrate : (Class IIa, Level of Evidence B)

❑ Hydralazine and isosorbide dinitrate should be considered in black patients with LVEF ≤35% or with an LVEF<45% combined with a dilated left ventricle in NYHA class III-IV despite therapy with an ACE-I (or ARNI), a beta-blocker and an MRA to reduce the risk of HF hospitalization and death.1

Hydralazine, isosorbide dinitrate (Class IIb, Level of Evidence B):

❑ Hydralazine and isosorbide dinitrate may be considered in patients with symptomatic HFrEF who unable to tolerate any of an ACE-I, an ARB, or ARNI (or they are contraindicated) to reduce the risk of death

Digoxin: (ClassIIb, Level of Evidence B)

❑ Digoxin may be considered in patients  with symptomatic HFrEF in sinus rhythm despite treating with an ACE-I (or ARNI), a beta- blocker and an MRA, to reduce the risk of hospitalization (both all-cause and HF hospitalizations)

The above table adopted from 2021 ESC Guideline

[2]

### Diuretics

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* Loop diuretics is recommended to reduce the signs and/or symptoms of congestion in patients with HFrEF.[16]
* The effects of diuretics on morbidity and mortality have not been studied in RCTs.
* Loop diuretics and thiazide diuretics appear to reduce the risk of death and worsening HF compared with a placebo.
* Diuretics can improve exercise capacity.[17]
* Loop diuretics and thiazides act synergistically and may be used to treat diuretic resistance.
* ARNI, MRAs, and SGLT2 inhibitors may also possess diuretic properties.
* Maintaining the euvolemia state is the aim of diuretic therapy with the lowest doses.[18]
* Patients should be trained to self-adjust their diuretic dose based on monitoring of symptoms/signs of congestion and daily weight measurements.

### Angiotensin II type I receptor blockers

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* ARBs are recommended for patients who cannot tolerate ACE-I or ARNI because of serious side effects.
* CHARM-Alternative study showed candesartan reduced cardiovascular deaths and HF hospitalizations in patients who were not receiving an ACE-I due to previous intolerance.[19]
* In the Val-HeFT trial, Valsartan, in addition to usual therapy, including ACE-I, reduced HF hospitalizations.[20]
* ARBs have not reduced all-cause mortality in any trial.

### If -channel inhibitor

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* Ivabradine slows heart rate by inhibition of the If channel in the sinus node only in patients with sinus rhythm.[21]
* Ivabradine reduced cardiovascular mortality and HF hospitalization in patients with symptomatic HFrEF with an LVEF <_35%, with HF hospitalization in recent 12 months, in sinus rhythm (SR) and with a heart rate≥70 b.p.m.[22]
* Ivabradine has survival benefit.
* Before to considering ivabradine, uptitrate beta-blocker therapy to maximally tolerated doses is recommended.

### Combination of hydralazine and isosorbide dinitrate

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* In black patients with HFrEF and NYHA classes III-IV, combination of hydralazine and isosorbide dinitrate to conventional therapy (an ACE-I, a beta-blocker, and an MRA) reduced mortality and HF hospitalizations.
* In symptomatic patients with HFrEF who cannot tolerate any of an ACE-I, ARNI, or an ARB (or if they are contraindicated), combination of hydralazine and isosorbide dinitrate may be considered to reduce mortality.[23]

### Digoxin

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* Digoxin may be considered in patients with HFrEF in sinus rhythm to reduce the risk of hospitalization.
* In the DIG trial, digoxin was not effective on mortality.
* The effects of digoxin in patients with HFrEF and AF have not been studied in RCTs. However, higher risk of events were observed in patients with AF  receiving digoxin.[24][25]
* Another meta-analysis concluded that digoxin has no deleterious effect on mortality in patients with AF and HFrEF.
* So, in patients with symptomatic HF and AF, digoxin may be useful for the treatment of patients with HFrEF and AF with rapid ventricular rate, when other therapeutic options are failed.
* Digoxin has a narrow therapeutic window and so levels should be checked for maintaing a serum digoxin concentration <1.2 ng/mL.[26]
* Caution should also be exercised in patients as followes:

* Females
* The elderly
* Frail
* Hypokalaemia
* Malnourishment
* Reduced renal function

### Soluble guanylate cyclase receptor stimulator

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* The VICTORIA study investigated the efficacy and safety of the oral soluble guanylate cyclase receptor stimulator, vericiguat, in patients with HFrEF and recently decompensated CHF.[27]
* Use of vericiguat was associated with reduced hospitalization. However, there were no reduction in all-cause or cardiovascular mortality.
* Vericiguat may be considered, in addition to standard therapy for HFrEF, to reduce the risk of cardiovascular mortality and hospitalizations for HF.

### Cardiac myosin activator

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* the efficacy and safety of the cardiac myosin activator, omecamtiv mecarbil, in HFrEF patients, was assessed by The GALACTIC-HF study.[28]
* There was no significant reduction in cardiovascular mortality.
* Currently, there is no license for use of this drug.
* This drug may be considered in the future in addition to standard therapy for HFrEF to reduce the risk of cardiovascular mortality and hospitalization.

## Management of chronic heart failure

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### Serial clinical evaluation , titration of Medications

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### Intensification 2-4 months, (1-4 weeks cycles)

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* In the presence of volume overload, adjusting diuretic dose and reevaluation in 1-2 weeks
* In the setting of stable euvolumic status, medications initiation, increase, switch dose and follow-up in 1-2 weeks and checking basic metabolites panel, repeating cycles until no change in clinical status and reached appropriate titration

### Assessment of response to medications and cardiac remodeling

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* Repeating BNP, pro BNP and basic metabolic panel
* Pepeating ECG, Echocardiography
* Refferal eligible patients to electrophysiology specialist for CRT or ICD implantation

### Lack of response, instability

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* Referral to advanced heart failure specialist if there are:
* Use of IV inotropes
* NYHA 3B, 4, or persistently high level of natrioretic peptide
* End organ dysfunction
* LVEF ≤ 35%
* Defibrillator shocks
* Hospitalization > 1 day
* Edema despite increase dose of diuretics
* Low blood pressure, high heart rate
* Intolerance to medications

### Assessment of response to medications

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* Repeating laboratory tests such as NT pro BNP, BNP, electrolytes
* Repeating ECG
* Repeating echocardiography for evaluation of structure, function
* Referral to electrophysiologic for implantation of ICD, CRT in eligible patients

## References

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1. ↑ Maddox TM, Januzzi JL, Allen LA, Breathett K, Butler J, Davis LL, Fonarow GC, Ibrahim NE, Lindenfeld J, Masoudi FA, Motiwala SR, Oliveros E, Patterson JH, Walsh MN, Wasserman A, Yancy CW, Youmans QR (February 2021). "2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee". J Am Coll Cardiol. 77 (6): 772–810. doi:10.1016/j.jacc.2020.11.022. PMID 33446410 Check `|pmid=` value (help).
2. ↑ 2.0 2.1 McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland J, Coats A, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam C, Lyon AR, McMurray J, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano G, Ruschitzka F, Kathrine Skibelund A (September 2021). "2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure". Eur Heart J. 42 (36): 3599–3726. doi:10.1093/eurheartj/ehab368. PMID 34447992 Check `|pmid=` value (help). Vancouver style error: initials (help)
3. ↑ Willenheimer R, van Veldhuisen DJ, Silke B, Erdmann E, Follath F, Krum H, Ponikowski P, Skene A, van de Ven L, Verkenne P, Lechat P (October 2005). "Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III". Circulation. 112 (16): 2426–35. doi:10.1161/CIRCULATIONAHA.105.582320. PMID 16143696.
4. ↑ Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (September 1999). "The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators". N Engl J Med. 341 (10): 709–17. doi:10.1056/NEJM199909023411001. PMID 10471456.
5. ↑ McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (September 2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure". N Engl J Med. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. PMID 25176015.
6. ↑ Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, Rouleau JL, Swedberg K, Lefkowitz M, Shi VC, Desai AS, McMurray J, Solomon SD (May 2017). "Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial". Lancet Diabetes Endocrinol. 5 (5): 333–340. doi:10.1016/S2213-8587(17)30087-6. PMC 5534167. PMID 28330649. Vancouver style error: initials (help)
7. ↑ Damman K, Gori M, Claggett B, Jhund PS, Senni M, Lefkowitz MP, Prescott MF, Shi VC, Rouleau JL, Swedberg K, Zile MR, Packer M, Desai AS, Solomon SD, McMurray J (June 2018). "Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure". JACC Heart Fail. 6 (6): 489–498. doi:10.1016/j.jchf.2018.02.004. PMID 29655829. Vancouver style error: initials (help)
8. ↑ Desai AS, Vardeny O, Claggett B, McMurray JJ, Packer M, Swedberg K, Rouleau JL, Zile MR, Lefkowitz M, Shi V, Solomon SD (January 2017). "Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial". JAMA Cardiol. 2 (1): 79–85. doi:10.1001/jamacardio.2016.4733. PMID 27842179.
9. ↑ Vardeny O, Claggett B, Kachadourian J, Desai AS, Packer M, Rouleau J, Zile MR, Swedberg K, Lefkowitz M, Shi V, McMurray J, Solomon SD (March 2019). "Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial". Eur J Heart Fail. 21 (3): 337–341. doi:10.1002/ejhf.1402. PMC 6607492 Check `|pmc=` value (help). PMID 30741494. Vancouver style error: initials (help)
10. ↑ DeVore AD, Braunwald E, Morrow DA, Duffy CI, Ambrosy AP, Chakraborty H, McCague K, Rocha R, Velazquez EJ (February 2020). "Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial". JAMA Cardiol. 5 (2): 202–207. doi:10.1001/jamacardio.2019.4665. PMC 6990764 Check `|pmc=` value (help). PMID 31825471.
11. ↑ Wachter R, Senni M, Belohlavek J, Straburzynska-Migaj E, Witte KK, Kobalava Z, Fonseca C, Goncalvesova E, Cavusoglu Y, Fernandez A, Chaaban S, Bøhmer E, Pouleur AC, Mueller C, Tribouilloy C, Lonn E, A L Buraiki J, Gniot J, Mozheiko M, Lelonek M, Noè A, Schwende H, Bao W, Butylin D, Pascual-Figal D (August 2019). "Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study". Eur J Heart Fail. 21 (8): 998–1007. doi:10.1002/ejhf.1498. PMID 31134724. Vancouver style error: missing comma (help)
12. ↑ McMurray J, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman C, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM (November 2019). "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction". N Engl J Med. 381 (21): 1995–2008. doi:10.1056/NEJMoa1911303. PMID 31535829. Vancouver style error: initials (help)
13. ↑ Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F (October 2020). "Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure". N Engl J Med. 383 (15): 1413–1424. doi:10.1056/NEJMoa2022190. PMID 32865377 Check `|pmid=` value (help).
14. ↑ Jackson AM, Dewan P, Anand IS, Bělohlávek J, Bengtsson O, de Boer RA, Böhm M, Boulton DW, Chopra VK, DeMets DL, Docherty KF, Dukát A, Greasley PJ, Howlett JG, Inzucchi SE, Katova T, Køber L, Kosiborod MN, Langkilde AM, Lindholm D, Ljungman C, Martinez FA, O'Meara E, Sabatine MS, Sjöstrand M, Solomon SD, Tereshchenko S, Verma S, Jhund PS, McMurray J (September 2020). "Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF". Circulation. 142 (11): 1040–1054. doi:10.1161/CIRCULATIONAHA.120.047077. PMC 7664959 Check `|pmc=` value (help). PMID 32673497 Check `|pmid=` value (help). Vancouver style error: initials (help)
15. ↑ Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B (January 2021). "Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure". N Engl J Med. 384 (2): 117–128. doi:10.1056/NEJMoa2030183. PMID 33200892 Check `|pmid=` value (help).
16. ↑ Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner-La Rocca HP, Martens P, Testani JM, Tang W, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ (February 2019). "The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology". Eur J Heart Fail. 21 (2): 137–155. doi:10.1002/ejhf.1369. PMID 30600580. Vancouver style error: initials (help)
17. ↑ Faris R, Flather M, Purcell H, Henein M, Poole-Wilson P, Coats A (February 2002). "Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials". Int J Cardiol. 82 (2): 149–58. doi:10.1016/s0167-5273(01)00600-3. PMID 11853901.
18. ↑ Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simões MV, Silvestre OM, Ribeiro A, Moura LZ, Beck-da-Silva L, Prado D, Sant'Anna RT, Bridi LH, Zimerman A, Raupp da Rosa P, Biolo A (November 2019). "Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial". Eur Heart J. 40 (44): 3605–3612. doi:10.1093/eurheartj/ehz554. PMID 31424503. Vancouver style error: initials (help)
19. ↑ Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K (September 2003). "Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial". Lancet. 362 (9386): 772–6. doi:10.1016/S0140-6736(03)14284-5. PMID 13678870.
20. ↑ Cohn JN, Tognoni G (December 2001). "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". N Engl J Med. 345 (23): 1667–75. doi:10.1056/NEJMoa010713. PMID 11759645.
21. ↑ Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil JC, Swedberg K, Tavazzi L (January 2013). "Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study". Clin Res Cardiol. 102 (1): 11–22. doi:10.1007/s00392-012-0467-8. PMID 22575988.
22. ↑ Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L (September 2010). "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study". Lancet. 376 (9744): 875–85. doi:10.1016/S0140-6736(10)61198-1. PMID 20801500.
23. ↑ Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN (November 2004). "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure". N Engl J Med. 351 (20): 2049–57. doi:10.1056/NEJMoa042934. PMID 15533851.
24. ↑ Vamos M, Erath JW, Hohnloser SH (July 2015). "Digoxin-associated mortality: a systematic review and meta-analysis of the literature". Eur Heart J. 36 (28): 1831–8. doi:10.1093/eurheartj/ehv143. PMID 25939649.
25. ↑ Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, Mahaffey KW, Hankey GJ, Berkowitz SD, Nessel CC, Fox KA, Califf RM, Piccini JP, Patel MR (June 2015). "Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)". Lancet. 385 (9985): 2363–70. doi:10.1016/S0140-6736(14)61836-5. PMID 25749644.
26. ↑ Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM (February 2003). "Association of serum digoxin concentration and outcomes in patients with heart failure". JAMA. 289 (7): 871–8. doi:10.1001/jama.289.7.871. PMID 12588271.
27. ↑ Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam C, Ponikowski P, Voors AA, Jia G, McNulty SE, Patel MJ, Roessig L, Koglin J, O'Connor CM (May 2020). "Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction". N Engl J Med. 382 (20): 1883–1893. doi:10.1056/NEJMoa1915928. PMID 32222134 Check `|pmid=` value (help). Vancouver style error: initials (help)
28. ↑ Teerlink JR, Diaz R, Felker GM, McMurray J, Metra M, Solomon SD, Legg JC, Büchele G, Varin C, Kurtz CE, Malik FI, Honarpour N (April 2020). "Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF". JACC Heart Fail. 8 (4): 329–340. doi:10.1016/j.jchf.2019.12.001. PMID 32035892 Check `|pmid=` value (help). Vancouver style error: initials (help)

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